SE425973B - PROCEDURE FOR PREPARING BASIC SUBSTITUTED ALKYLTEOPHYLINE DERIVATIVES - Google Patents

Description

The 7800500-6 atom may be protected by a benzyl group.

The hydrogenation is carried out in water, methanol, ethanol or water-alcohol mixtures.

A major inconvenience in the hydrogenation of such compounds, however, is that one must work with high dilution, then. the initial ketone is pronouncedly insoluble. If, for example, a starting ketone of formula B is used in which the secondary basic nitrogen atom contains a benzyl group as protecting group, this benzyl group is first cleaved during the hydrogenation so that the almost insoluble ketone formed itself is very often precipitated at high temperatures and high dilution. in the reaction vessel and the catalyst surface are thereby inactivated so that the per se already difficult-to-hydrate keto group is now reduced extremely slowly and imperfectly. The inconveniences described are particularly noticeable on a technical and production scale.

As can be seen, for example, from German Pat. No. 1,545,725, the hydrogenation of ketones of formula B (Examples 1, 2, 6 and 7) requires 25 to 72 times the amounts of solvent in the form of mixtures. Even when using the dimethylformamide used exceptionally for catalytic hydrogenation of sparingly soluble substances, for example, the precursor of Example 2 must be dissolved in 15-fold amount of this solvent. At the optimum temperatures of 60-70 ° C for this reaction, however, even under these conditions, the deboned ketone B precipitates, whereby the rehydration, especially at large batches, is made extremely difficult: at the required hydrogenation times of approx. After 48 hours, colored by-products are formed and the final, still strongly ketone-containing product formed must be post-hydrated and recrystallized under large losses in order to obtain the purity required for pharmaceutical use. A large-scale technical production is in this way very expensive and uneconomical.

The invention relates to a process for the preparation of basically substituted alkyl theophylline derivatives of the general formula o wherein 2k represents a straight or branched alkylene chain. having 2 to 4 carbon atoms and R represents hydrogen or a methyl group, by catalytic hydrogenation of compounds of the general formula 3 vsoosoo-6 (OH) _, _ N-Alk-- N11- CH-- CJ å !! n CII wherein Alk and R are as defined above and wherein the phenolic hydroxy group and / or the secondary basic nitrogen atom may contain protecting groups and is characterized in that the hydrogenation takes place in a solvent of the general formula RI RIU-_ C _ ÉR "III O wherein R ', R "and R"' may be the same or different and represent alkyl groups having 1 to 3 carbon atoms and wherein R 'together with R "' may also form an alkylene bridge having 3 to 4 carbon atoms.

If this reaction product still contains protecting groups, these can be cleaved off in the usual way.

In formulas I and II, Alk especially represents the following groups: -OH2-CH2-; - (CH2) 3-; - (CH2) 4-; -CH2-1H-CH2; -CH2-CH2-? H-.

CH3 CH3 It is surprising that the difficulties already described do not occur if the hydrogenation is carried out in a solvent of the general formula III. If R 'and R "' in formula III together form an alkylene bridge having 3 or 4 carbon atoms, the general formula for this case is: <° íï \.

C = O & \ IIIa * f / R "_ n = 3 or 4, R" = CH3 or C2H5. The preferred solvents of the structure described are dimethylacetamide, and N-methylpyrrolidone. Mixtures of these commercially available solvents with water are also useful, the water content not to exceed 50%. For example, a water content of up to 30% is possible. Preferably, the water content amounts to between 0 and 10%.

According to the process of the invention, the ketones of general formula II are dissolved in 5- to 15-fold amount of a solvent characterized by formula III and hydrogenated after addition of the hydrogenation catalyst at temperatures between 20 and 100 ° C. The reaction can be carried out under pressure (for example up to 50 bar, preferably 2 - 10 bar) or even without pressure. Should the water uptake be greatly reduced due to the fact that during each hydration sometimes contact toxin traces are present, it is possible to filter and, after the addition of a new catalyst, hydrate in the end. In the older process this is not possible as in the slower reaction the precipitating starting ketone can no longer be easily separated from the catalyst. For work-up, evaporation of the filtered hydrogenation solution in vacuo is sufficient to purify the residue; customary manner such as recrystallization, reprecipitation or boiling with a solvent, preferably an alcohol. Recovery of the solvent by evaporation of the reaction solution is easily possible then. the toluene formed during the hydrogenation of starting ketones containing benzyl oxide groups can be easily separated (high boiling point difference between toluene and the solvent used).

The reduction corresponding to the process according to the invention takes place with catalytically activated hydrogen using customary metal catalysts, which can be used for the reduction of an oxo group to a hydroxy group. The catalysts can be used with or without a support. Particularly suitable are noble metal catalysts such as palladium (for example palladium-kcl, palladium on barium sulphate), platinum and platinum dioxide.

Hydrogenolytically cleavable protecting groups, which may be present, are generally cleaved at the reduction if this is done with hydrogen in the presence of palladium catalysts. If the protecting groups present are not cleaved during the reaction, these can be removed, for example, when the reduction of the oxo group is completed by treatment with hydrogen in the presence of palladium catalysts or customary hydrolysis.

In the process according to the invention, it is often suitable to protect the phenolic hydroxyl group as well as the secondary amino groups with protecting groups known per se. Often such protecting groups are necessary already for the production of the starting compounds. These protecting groups are easily cleavable from the final product. These are either easily solvolytically cleavable acyl groups or hydrogenating cleavable groups such as, for example, benzyl groups. The solvolytically cleavable protecting groups are cleaved, for example, by saponification with dilute acid at room temperature or even briefly boiling. Depending on the nature of the protection group, however, cleavage takes place already during the procedural reaction. The latter is the case, for example, when the secondary amino group and possibly also the phenolic hydroxy group is protected with a benzyl group or a carboxy group and palladium catalysts are used. If the protecting groups are not cleaved during the reaction, a simple post-treatment of the reaction product is required, the cleavage of the protecting group (s) taking place, for example, under the conditions stated above.

As the protecting group for the secondary amino group, there are, for example: O 6 -arylalkyl groups such as a benzyl group, OC-phenylethyl group, trityl residue, benzyl groups substituted in the benzene nucleus such as, for example, the p-bromo or p-nitrobenzyl group; hydroxycarbonyl radicals such as a carbobenzoxy group, a carbobenziothio group, tert-butylhydroxycarbonyl radical; a trifluoroacetyl group, a phthalyl residue, tert-butylcarboxy group, p-toluenesulfonyl residue and the like. For the phenolic hydroxy group, in principle the same residues are in question; furthermore, for example, simple acyl groups are also suitable here, such as, for example, lower alkanoyl residues such as acetyl, formyl or lower carbalkoxy.

In summary, the significant advantages of the new process over known processes are: Soluble intermediates do not precipitate during the reaction. 2. Higher yields (eg 94.5% instead of 66.5% corresponding to Example 2 of German Patent Specification 1,545,725. 3. Shorter hydrogenation time. 4. Higher concentration. Thus in the same reaction vessel is significantly higher possible rates whereby solvents and manufacturing costs can be saved.

No difficulties arise with batch enlargement.

Reprocessing is easier than before.

Higher purity of the final product is achieved. The recovery of the solvent is easier.

The invention is further illustrated by the following examples in which the temperature refers to degrees Celsius.

OO fl Oxur. . . . 7800500-6 Example gel 1 - 500 g of 7- [3- [2- (3,5-allyaroxyphenyl) -2- [xo-ethylbenzylamino] -propyl] -theophylline hydrochloride were dissolved in 5 liters of dimethylacetamide. 25 g of a 107 μg palladium-carbon catalyst were added, heated to 700 and hydrogenated with stirring at this temperature and 2 bar pressure until the hydrogenation rate was noticeably slower (about two hours). The mixture was then filtered and, after adding an additional 25 g of the palladium catalyst, it was finally hydrogenated at 6 bar (2 to 3 hours). The mixture was filtered, distilled off in a water jet vacuum and most of the solvent was added, and 8 liters of ethanol were added. The solution was cooled for 12 hours with running water and the precipitated substance was filtered off with suction.

Now boil for 1 hour while stirring and passing nitrogen with 2 liters of methanol, cooled to 25 ° and filtered off with suction. After drying in vacuo at 55 °, 391 g (= 94.5% of theory) of pure 7β- [2- (3H5-dihydroxy) phenyl-2-hydroxyethylamino] -propyl-theophylline hydrochloride were obtained. 265 °.

Example 2 50 g of the starting material used in Example 1 were dissolved in 0.4 liters of N-methylpyrrolidone- (Z) and hydrogenated after the addition of 5 g of a palladium-carbon catalyst without overpressure at 75 °. After complete hydrogen uptake was filtered, the solvent was distilled off to about 5 Torr on. water bath and boil the residue for 1 hour while stirring with 90% ethanol. After standing for 20 hours at 20 °, it was filtered off, washed with ethanol and dried. Yield: 31 g (= 75% of theory) of the product obtained according to Example 1. Melting point 262 - 264 °.

Example gel 3,850 g of 7- {2- [2- (3,4-dibenzyloxyphenylMZ-oxo-ethylbenzylamino] -ethyl} -theophylline hydrochloride was hydrogenated in 10 liters of dimethylacetamide with the addition of 60 g of a palladium-carbon catalyst at 5 bar hydrogen pressure and 50 ° C. The solvent is distilled off in vacuo and the residue is boiled while stirring and passing nitrogen for 1 hour with 8 liters of absolute ethanol. After standing for 15 hours at room temperature, the mixture is filtered off and boiled again with 5 liters of ethanol in the manner indicated above. The aspirated and dried substance is analytically pure. 46 g (= s9.2 =, fl. Of the theoretical) were obtained. 7- {2- [2- (3,4-aliquots ) -2-hydroxyethylamino] -ethyl-theophylline hydrochloride, m.p. 186-188 °.

The starting material can be obtained as follows: A solution of 643 g of 3,4-dibenzyloxy-O-bromoacetophenone and 980 g of 7- (Z-benzylaminoethyl) -theophylline in 10 liters of toluene was boiled for 4 hours with stirring at reflux. The mixture was allowed to cool to 60 °, the hydrobromide formed was filtered off with suction, washed with 0.5 liters of toluene and allowed to stand in the refrigerator for 15 hours. The crystallized base was filtered off with suction, suspended in methanol and transferred by stirring with 130 ml of methanolic hydrochloric acid into the hydrochloride. After 10 hours, the mixture was filtered off, washed with cold methanol and dried at 60 °. 834 g (= 78.4% of theory) of γ- {2- [2- (3,4-dibenzyloxyphenol) -2-oxoethylbenzylamino] -ethyl] -pheophylline-hyarokioria were obtained, m.p. 170 DEG-174 DEG.

Example 4 In 12 g of 7- {3- [2- (3,5-aminaroxyphenyl) -2- [x-ethylamino] propyl} -theophylline hydrochloride was hydrogenated in 200 ml of diethyl acetamide with the addition of 0.8 g of potassium carbon sçz-ig) via so - 7o °. After absorbing the calculated amount of hydrogen, it was filtered, evaporated in vacuo and the residue was boiled with 90% ethanol for 1 hour. The next day they drained, washed with ethanol and dried. 10.1 g (85%) of 7- {§- [2- (3,5-dihydrophenyl) -2-hydroxyethylamine] -propyl} -theophylline hydrochloride were obtained. melting point 262 - 2s5 °.

Claims (2)

A process for the preparation of basic substituted alkyl theophylline derivatives of the general formula <<> fl> 2 CH wherein Alk represents a ralc or branched alkylene chain having 2. - 4 carbon atoms and R represents hydrogen or a methyl group by catalytic hydrogenation of compounds of the general formula ° (Ofog CHTN \ --A11 <--N1-1 - cH-- c- Å /: lä y) __ 'II 0 I: \ N. wherein Alk and R have the meaning given above and wherein the phenolic hydroxymp and / or the secondary basic nitrogen atom may contain protecting groups, characterized in that the hydrogenation takes place in a solvent of the general formula NZR 'RH! III wherein R ', R "and 12"' are the same or different and form alkyl groups having 1 to 2 carbon atoms and wherein R 'together with R "" may also form an alkylene bridge having 3 or 4 A process according to claim 1, characterized in that the secondary basic nitrogen atom and / or the two phenolic hydroxy groups contain benzyl groups as protecting groups.